This invention relates to a method of treating Acquired Immune Deficiency Syndrome (AIDS) in humans using antisense oligodeoxynucleoside methylphosphonates.
It is known that organisms have exploited a wide variety of mechanisms for regulating gene expression. Green, P. J., et al., Ann. Rev. Biochem 55: 569-597 (1986) reported that naturally occurring regulatory genes direct the synthesis of RNA which can directly control gene expression. The term "antisense RNA" has been coined to describe this regulatory RNA. Antisense RNA is complementary to and therefore can form base pairs with a specific mRNA. The naturally occurring antisense RNA discovered to date has been in bacterial systems. The discovery of this natural phenomenon has led to the exploitation of antisense RNA and DNA to inhibit the expression of a wide variety of gene products by interference with activities such as pre-mRNA splicing, mRNA transport to the cytoplasm, and translation of the mRNA itself. Of particular interest is the use of nucleic acid sequences complementary to viral gene targets in the human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV-III/LAV), the etiological agents of AIDS..sup.1/ FNT .sup.1/ A., Hollander, H. and Stobo, J. Ann. Rev. Med. 36, 545-562 (1985); Wong-Staal, F. and Gallo, R. C., Nature 317, 395-403 (1985); Rabson, A. B. and Martin, M. A. Cell 40, 477-480 (1985).
It is known that HIV, a retrovirus, infects T-lymphocytes by recognizing the T4 antigen,.sup.2/ and that brain cells and macrophages are also targets for the viral infection..sup.3/ The viral sequence of HIV has been determined to include genes for the structural proteins of the virus which are designated gag, pol, and env. These genes are bounded by the long terminal repeats (LTRs). There are also accessory genes in the HIV genome which are involved in controlling virus replication, including at least three genes which code for trans-activator (tat) regulatory protein..sup.4/ FNT .sup.2/ Dalgleish, A. B. et al., Nature 312, 277-284 (1985); Maddon, P. J., et al., Cell 47, 333-348 (1986); McDougal, J. S., et al., J. Immunol. 135, 3151-3162 (1985). FNT .sup.3/ Epstein, L. G., et al., AIDS Res. 1, 447-454 (1985); Ho, D. D., et al., N. Eng. J. Med/ 313, 1498-1504 (1985); Koenig, S., et al., Science 233, 1089-1093 (1986 ); Levy, J. A., et al., Lancet 11, 586-588 (1085); Sharer, L. R., et al., Human Path. 17, 271-284 (1986); Shaw, G. M., et al., Science 227, 177-182 (1985). FNT .sup.4/ Sodroski, J., et al., Nature 321, 412-417 (1986); Rosen, C. A., et al., Nature 319, 555-559 (1986); Fischinger, P. J. and Bolognesi, D. P. in AIDS (ed. DeVita, Jr., V. T., Helman, S. and Rosenberg, S. A.) 55-58 (Lippincott Co., Philadelphia, Pa., 1985).
Oligodeoxyribonucleoside methylphosphonates (OMPs) are nucleic acid analogs in which a 3'-5' methylphosphonate linkage replaces the phosphodiester linkage found in naturally occurring nucleic acids. OMPs maintain the selectivity of complementary pairing exhibited by standard oligodeoxyribonucleotides and can be used as antisense agents. Miller, P. S., et al., Biochimie 67: 769-776 (1985) have shown that oligonucleoside methylphosphonates complementary to various regions of the rabbit globin mRNA inhibit translation of the RNA in a reticulocyte cell-free system. Herpes simplex type I virus has also been selectively inhibited using an antisense OMP targeted to its regulatory immediate early gene resulting in 99% reduction in infectious virus and a 75% reduction in viral DNA synthesis. Smith, C. C., et al., Biochemistry 83: 2787-2791 (1986).